Mast cells have long been associated with debilitating, and occasionally fatal, hypersensitivities to innocuous substances like peanuts, shellfish or lifesaving drugs such as penicillin. More recently, researchers have identified roles for mast cells in host defense, scavenger functions targeted against venoms and toxins, and cancer and autoimmune pathologies. Pain is one of the cardinal signs of the inflammatory response and is potentiated by sensitization of the nociceptive neurons. The roles of inflammatory cytokines such as TNF-a, IL-6, 8, 12 and final mediators such as endothelins and sympathetic amines have been described in rodent models of hypernociception. While neutrophil migration and the adaptive response have been identified as cellular immune components of inflammatory hypernociception and other experiments have suggested that mast cells may also be involved, the precise roles of mast cells in this process have not been thoroughly characterized. This R15 application proposes research that will test the hypothesis that mast cells are critical initiators of the inflammatory pain cascade in hypernociception models in mice. Specific Aim 1 investigates whether mast cells are necessary for hypernociception in a compound 48/80 (a mast cell secretagogue) model of innate inflammatory pain and Specific Aim 2 aims to establish a mast-cell specific model of antibody-mediated pain that can then be used to further dissect the contributions of mast cells to the initiation of allergic hypernociception. Taken together, the proposed studies aim to elucidate the roles of an intriguing population of sentinel immune cells in pain - a novel context in which their function has yet to be characterized. PUBLIC HEALTH RELEVANCE: Pain is a cardinal sign of inflammation. Mast cells are immune cells that have complex functions in host defense, allergy, autoimmunity and cancer, and may also play critical roles in the initiation of the inflammatory pain cascade. Resolving the potential role/s for mast cells in nociception will enhance our understanding of pain processes and provide knowledge about a novel aspect of mast cell physiology.